1. Field of the Invention
The present invention provides novel nanoparticle compositions comprising a PSMA inhibitor, linker, nanoparticle and biologically active compound. The compositions of the invention are useful for providing methods of treating disorders, including cancer.
2. Background
Prostate cancer is the most commonly diagnosed non-cutaneous malignancy in American men and remains uniformly fatal once it undergoes metastasis (Jemal, A., et al. Cancer statistics, 2006. Ca-a Cancer Journal for Clinicians, 56: 106-130, 2006). Androgen ablation therapy is effective palliative therapy, but in all men tumor progression eventually occurs even when completely androgen-deprived (e.g. inhibition of both testicular and adrenal androgens) (Crawford, E. D., et al. N Engl J Med, 321: 419-424, 1989). Traditionally, prostate cancer was thought to be relatively resistant to cytotoxic chemotherapies administered following androgen ablation (Yagoda, A. and Petrylak, D. Cancer, 71: 1098-1109, 1993). However, two recent studies demonstrated a modest survival benefit in men with hormone refractory metastatic disease treated with docetaxel (Petrylak, D. P., et al. N Engl J Med, 351: 1513-1520, 2004; Tannock, I. F., et al. N Engl J Med, 351: 1502-1512, 2004). As with other cytotoxic therapies, docetaxel is associated with systemic toxicity that limits both the total dose and duration of therapy that can be administered (Petrylak, D. P., et al. N Engl J Med, 351: 1513-1520, 2004; Tannock, I. F., et al. N Engl J Med, 351: 1502-1512, 2004). To improve the therapeutic window, a number of approaches have been explored to target cytotoxic agents like docetaxel selectively to tumor with the goal of higher tumor concentration and lessening of toxicity to normal tissues. In this regard, various prostate tissue specific surface proteins have been evaluated as potential binding targets to improve tumor uptake and retention of therapeutic agents.
The most extensively characterized surface protein has been prostate-specific membrane antigen (PSMA). PSMA is highly expressed by prostate cancer compared to most normal tissue (Wright, G. L., et al. Urol Oncol, 1: 18-28, 1995; Israeli, R. S., et al. Cancer Res, 54: 1807-1811, 1994; Chang, S. S., et al. Cancer Res, 59: 3192-3198, 1909; Silver, D. A., et al. Clin Cancer Res, 3: 81-85, 199. PSMA expression has also been demonstrated to increase following androgen ablation (Montgomery, B. T., et al. Prostate, 21: 63-73, 1992; Wright, G. L., et al. Urology, 48: 326-334, 1996). Multiple studies have documented that PSMA is also expressed in the neovasculature of most solid tumors, but not in the vasculature of normal tissues (Israeli, R. S., et al. Cancer Res, 54: 1807-1811, 1994; Chang, S. S., et al. Cancer Res, 59: 3192-3198, 1999). PSMA is a carboxypeptidase and is relatively unique in its ability to function as both an N-acetylated alpha-linked dipeptidase and a gamma glutamyl (i.e. folate) hydrolase (Carter, R. E., et al. Proc Natl Acad Sci USA, 93: 749-753, 1996; Pinto, J. T., et al. Clin Cancer Res, 2: 1445-1451, 1996). Therefore, PSMA has been an attractive target for both targeted drug delivery and imaging. PSMA targeting approaches include the use of PSMA peptide substrates (Mhaka, A., et al. Cancer Biol Ther, 3: 551-558, 2004), PSMA-binding peptides (Aggarwal, S., et al. Cancer Res, 66: 9171-9177, 2006; Lupold, S. E. and Rodriguez, R. Mol Cancer Ther, 3: 597-603, 2004), RNA aptamers (Farokhzad, O. C., et al. Proc Natl Acad Sci USA, 103: 6315-6320, 2006; Lupold, S. E., et al. Cancer Res, 62: 4029-4033, 2002) or anti-PSMA monoclonal antibody-cytotoxin conjugates (Nanus, D. M., et al. J Urol, 170: S84-88; discussion S88-89, 2003). Efforts have also been made to image PSMA-positive prostate tumors using labeled small-molecule peptidomimetic PSMA inhibitors (Foss, C. A., et al. Clin Cancer Res, 11: 4022-4028, 2005; Zhou, J., et al. Nat Rev Drug Discov, 4: 1015-1026, 2005) and monoclonal antibodies (Bander, N. H. Nat Clin Pract Urol, 3: 216-225, 2006; Lopes, A. D., et al. Cancer Res, 50: 6423-6429, 1990).
Previously Zhou et al reviewed a series of urea-based PSMA inhibitors with high picomolar to low nanomolar Ki values (Zhou, J., et al. Nat Rev Drug Discov, 4: 1015-1026, 2005). Radiolabeled versions of these inhibitors have been used to selectively image PSMA-expressing prostate cancer xenografts (Foss, C. A., et al. Clin Cancer Res, 11: 4022-4028, 2005). On the basis of these studies, we developed an approach to functionalize nanoparticles with a highly potent urea-based PSMA inhibitor which could enable homing of the nanoparticle to prostate cancer. The small-molecule inhibitor would allow for the generation of a highly decorated nanoparticle surface in which multiple ligand-protein binding interactions would produce an avidity effect that would enhance the binding of the nanoparticle to PSMA.
In a previous study, it was demonstrated that docetaxel could be readily encapsulated into poly(lactide-β-ethylene glycol-(β-lactide) (PLA-PEG-PLA) nanoparticles and that these nanoparticles exhibited in vivo efficacy (Chandran, S. S., Gerber, S. A., Rosen, M., and Denmeade, S. R. Formulation, in vitro efficacy and in vivo pharmacokinetics of polymeric nanoparticles bearing the natural toxin thapsigargin and its analog 12ADT. Manuscript in preparation). PLA-PEG-PLA was chosen as the controlled release system because its component polymers have been previously demonstrated to be biocompatible and have been extensively used in drug development (Greenwald, R. B., et al. Adv Drug Deliv Rev, 55: 217-250, 2003; Lee, J. S., et al. Eur J Pharm Biopharm, 59: 169-175, 2005; Li, S. and McCarthy, S. Biomaterials, 20: 35-44, 1999; Shive, M. S. and Anderson, J. M. Adv Drug Deliv Rev, 28: 5-24, 1997).
What is desired is to provide novel nanoparticle compositions comprising a biologically active material and PSMA inhibitors which are attached to the nanoparticle via a linker, while retaining high affinity to PSMA.